Neural Circuits and Behavior

Principal Investigator: Alexander FLEISCHMANN, CR1 Inserm

Genetic analysis of olfactory processing and function

Our laboratory is interested in the functional properties of neural circuits underlying olfactory sensory processing. We use a combination of molecular genetic, in vivo imaging and behavioral approaches in mice to understand the logic of odor coding at higher olfactory centers in the cortex.

Odor perception involves the recognition of odorants in the periphery as well as central mechanisms in the brain that allow the discrimination of odors and appropriate behavioral responses. Odorants are recognized by odorant receptors, expressed in olfactory sensory neurons in the nose. Odors activate subsets of sensory neurons and result in sparse and spatially invariant pattern of glomerular activity in the olfactory bulb, the first processing center of olfactory information in the brain. Information encoded by glomerular activity is then transmitted to higher olfactory centers in the cortex, which are thought to link odor representations to appropriate behavioral responses.

Central to understanding olfactory processing is the elucidation of the functional properties of the underlying neural circuits. In an effort to address this fundamental problem in sensory biology, we have altered the patterns of neural activity evoked by odors, by generating transgenic mice in which 95% of all sensory neurons express the same receptor. Two-photon in vivo imaging and behavioral analyses of these transgenic mice suggest a model of olfactory processing in which the recognition of patterns of neural activity, or contrast, is critical for odor detection.

To test this model, we employ state-of-the-art in vivo imaging approaches to reveal how defined patterns of glomerular activity are transformed into cortical odor representations. We take advantage of genetically modified mouse lines to characterize odor-evoked neural activity in defined neural cell types. And finally, we use optogenetic approaches to dissect the functional organization of this neural circuit and its role in olfactory-driven behaviors.

The laboratory uses an interdisciplinary approach, combining molecular mouse genetics, in vivo brain imaging and behavioral experiments, to address key questions in sensory biology and neural circuit function.

Fleischmann figure 1 partie C-D

Mice with a 'monoclonal nose' : perturbations in the olfactory map impair odor discrimination.
(A) Genetic strategy to express the M71 odorant receptor in all olfactory sensory neurons. Expression of the tetO-M71 transgene can be activated by the expression of tTA from the OMP locus. (B) Sensory neurons expressing the M71 transgene are marked by X-gal staining in a whole-mount preparation. OE: olfactory epithelium, VNO: vomeronasal organ, OB: olfactory bulb. (C and D) Staining with anti-M71 antibody of histological sections through the olfactory epithelium of control (C) and M71 transgenic mice (D).

Selected publications

- Diodato, A., Ruinart de Brimont, M., Yim, Y.S., Derian, N., Perrin, S., Pouch, J., Klatzmann, D., Garel, S., Choi, G.B. & Fleischmann, A. (2016), Molecular signatures of neural connectivity in the olfactory cortex. Nat Commun 7, 12238.

- Roland, B., Jordan, R., Sosulski, D.L., Diodato, A., Fukunaga, I., Wickersham, I., Franks, K.M., Schaefer, A.T. & Fleischmann, A. (2016), Massive normalization of olfactory bulb output in mice with a “monoclonal nose.” Elife 5, May 13;5. pii: e16335.

- Abdus-Saboor, I., Al Nufal, M.J., Agha, M.V., Ruinart de Brimont, M., Fleischmann, A. & Shykind, B.M. (2016), An Expression Refinement Process Ensures Singular Odorant Receptor Gene Choice. Curr. Biol. 26, 1083–1090. 

- Abdus-Saboor I., Fleischmann A. & Shykind B. (2014), Setting Limits: Maintaining order in a large gene family. Transcription 5, e28978.

- Fleischmann A., Abdus-Saboor I., Sayed A. & Shykind B (2013), Functional Interrogation of an Odorant Receptor Locus Reveals Multiple Axes of Transcriptional Regulation. PLoS Biol 11(5): e1001568. 

- Angelo K., Pimentel D., Pichler B., Fleischmann A., Rancz E. & Margrie T. (2012), A biophysical signature of network affiliation and sensory processing in mitral cells. Nature, Aug16;488(7411):375-8.

- Glinka M.E., Samuels B.A., Teillon J., Mei D.F., Shykind B.M., Hen R. & Fleischmann A. (2012), Olfactory deficits cause anxiety-like behaviors in mice. J. Neurosci., 32(19):6718-6725

- Choi G.B., Stettler D.D., Kallman B.R., Bhaskar S.T., Fleischmann A. & Axel R. (2011), Driving opposing behaviors with ensembles of piriform neurons. Cell 146:1004-1015

- Fleischmann A., Shykind B.M., Sosulski D.L., Franks K.M, Glinka M.E., Mei D.F., Yonghua S., Kirkland J., Mendelsohn M., Albers M.W. & Axel R. (2008), Mice with a "monoclonal" nose: perturbations in an olfactory map impair odor discrimination. Neuron. Dec 26; (60):1-14.

- Fleischmann A., Jochum W., Eferl R., Witowsky J. & Wagner E.F. (2003), Rhabdomyosarcoma development in mice lacking Trp53 and Fos: tumor suppression by the Fos protooncogene. Cancer Cell. Dec;4(6):477-82.

- Fleischmann A., Hvalby O., Jensen V., Strekalova T., Zacher C., Layer L.E., Kvello A., Reschke M., Spanagel R., Sprengel R., Wagner E.F. & Gass P. (2003), Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J Neurosci. Oct 8;23(27):9116-22. 


Group leader:
Fleischmann Alexander

Postdoctoral fellows & PhD Students:
Vieira Inès, PhD student
Meissner-Bernard Claire, PhD student

Master Students (M1-M2):
Simon Daste (2017)
Agatha Anet (2017)
Dmitri Bryzgalov (2017)

Technical staff:
Boyreau Adeline